P1095: COVID-19 VACCINE RESPONSES IN FOLLICULAR LYMPHOMA: DETERMINANTS OF HUMORAL AND CELLULAR IMMUNITY IN THE PETREA TRIAL OF FRONTLINE CHEMOIMMUNOTHERAPY
Authors: Yeong Jer Lim, Victoria Ward, Liam Farrell, Dean Naisbitt, Anthony Brown, Eloise Phillips, Paul Thomson, Melanie Oates, Richard Jackson, Andrew Morrison, Matthew Burns, Paul Klenerman, Lance Turtle, Malcolm Rhodes, Kate Robinson, Simona Gatto, Moya Young, Toby A Eyre, David W. Eyre, Susanna Dunachie, Eleanor Barnes, Andrew Pettitt
Journal: HemaSphere (2023)

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: The COVID-19 vaccination programme offered a unique opportunity to investigate how immunological responses to vaccination are influenced by cancer and its treatment without the confounding effects of prior immunisation and/or pathogen exposure. This is particularly relevant to patients with follicular lymphoma (FL) receiving initial therapy where there is a trade-off between long-term disease control and iatrogenic immunosuppression. The NCRI phase III PETReA trial provided an ideal platform for investigating COVID-19 vaccine responses in this setting. Aims: The dual aims of the study were to quantify antibody and T-cell responses to primary COVID-19 vaccination in patients with FL undergoing frontline chemoimmunotherapy (CIT) and elucidate sources of variation in these responses. Methods: The research was configured as a substudy of the NCRI PETReA trial (EudraCT number 2016-004010-10), a multicentre non-blinded phase III randomised controlled trial for patients with previously untreated advanced-stage FL. Patients received induction therapy with the anti-CD20 monoclonal antibody rituximab and either bendamustine or cyclophosphamide, vincristine and prednisolone, with (CHOP) or without (CVP) doxorubicin, and were randomly assignment to post-induction rituximab maintenance. COVID-19 vaccines (BNT162b2 or ChAdOx1) were administered before, during or after lymphoma treatment. Blood samples obtained after the first and second vaccine doses (V1 and V2) were analysed for antibodies and T-cells reactive to the SARS-CoV-2 spike protein using the Abbott Architect platform and ELISpot assay, respectively. A cohort of healthy controls (HCs) from the PITCH study (which employed the same metholodology) was used for comparison. Independent determinants of antibody and T-cell responses in the FL cohort were identified by multivariable analysis using a backwards stepwise procedure evaluated with Akaike’s Information Criterion (AIC). A p-value of 0.05 was used throughout to determine statistical significance. Results: Antibody but not T-cell responses were significantly lower in the FL cohort (n=58) compared with HCs (n=159). High/intermediate FLIPI-2 score, low serum IgA levels, bendamustine exposure and administration of V2 during lymphoma treatment were each identified as independent determinants of a low antibody response after V2. In contrast, low serum IgA levels and administration of V2 during lymphoma treatment predicted a higher T-cell response. Both types of immune response waned between 4 weeks and 6 months. In a multivariate model that estimated vaccine-induced immune responses for different combinations of predictive variables, several clinical scenarios were identified where positive or negative antibody or T-cell responses were predicted with ≥95% confidence. Summary/Conclusion: In FL patients undergoing frontline therapy, low serum IgA levels and administration of V2 during treatment are independent determinants of a reduced antibody response and an enhanced T-cell response following primary COVID-19 vaccination, while high tumour burden and bendamustine are additional determinants of a low antibody response. Our findings, which potentially extend to other vaccines and clinical settings, suggest that DNA/RNA vaccines may confer useful, if not full, clinical protection, even when administered during therapy that depletes B cells (rituximab) and CD4+ T cells (bendamustine). Keywords: Follicular lymphoma, COVID-19, Bendamustine, Rituximab